Background: Pancreatic adenosquamous carcinomas (PASC) are rare malignancies, with limited evidence regarding best treatment options. The Mayo Clinic Pancreatic Cancer SPORE Registry was utilized to compare/contrast outcomes for pancreatic cancers with a squamous component to pancreatic ductal adenocarcinoma (PDAC). Methods: Patients were identified from the SPORE Registry (2000-2019), were reviewed and confirmed by expert pathologists. Demographic and clinical information was ascertained from medical records and risk factor questionnaires. A case control study of patients with PASC vs PDAC was constructed. PASC patients were also followed for outcome and treatment records were extracted. Results: Of 2,584 total patients with pancreatic cancers, 45 cases of PASC and 2,438 with PDAC were identified. There were no differences in age (median 69 vs 67 years, p=0.42), sex (male 64.4vs 56.6%, p= 0.29), BMI (27.41 vs 27.78 kg/m2, P=0.50), or ever-smoking (61.0 vs 55.3%, P=0.47), with a borderline association with reported diabetes (17.8 vs 29.9%, p =0.08). Compared to PDAC, PASCs were more likely to involve the body/tail (48.9 vs 33.2%, p= 0.02) and had poorer overall survival, adjusted for age, gender, and stage (median 7.1 m vs 12.8m, HR 1.89, p=0.0004). Of 9 PASC pts treated with neoadjuvant intent, 4 were surgically resected, median survival was 7 months. Eleven pts underwent upfront surgery, with variable adjuvant treatments. Median OS post- surgery was 18m (range 7-51). Of 14 patients presenting with metastatic disease, median survival was 4.5 m (range 1-22). With regard to systemic chemotherapy, for neoadjuvant or metastatic disease median duration of treatment was 3 months (range 0.5-7m) for Gemcitabine + nab-paclitaxel (N=9) and also 3 months (range 2-6m) for FOLFIRINOX (N-13). Conclusions: The diagnosis of PASC carries an even poorer outcome than pancreatic adenocarcinoma. Tumors are more likely to arise in the distal pancreas, and patients may be less likely to report associated diabetes. Limited antitumor activity was noted with multi-agent chemotherapeutic regimens. Prospective trials will be needed to clarify choice of regimen in the future.